Weight loss by sodium-glucose co-transporter 2 inhibitor canagliflozin is followed by rebound in db/db mice but maintained in fat-fed mice via circadian rises in body temperature and locomotor activity

Sodium-glucose co-transporter 2 (SGLT2) inhibitors, diabetic medicines, induce glucosuria to lower glycemia and energy reserve, initially reducing weight. The weight-reducing capacity substantially differs between individuals, likely due to both social/psychological factors and physical/metabolic states. Exclusively analyzing the contribution of physical/metabolic states is difficult in humans but feasible in mice. To explore whether metabolic states can alter weight outcomes of SGLT2 inhibitor treatment, the impact of canagliflozin was studied comparatively in high-fat-diet-induced obese (DIO) mice and leptin-receptor-deficient db/db mice. Canagliflozin, orally administered, induced rapid reductions in glycemia and weight followed by elevated food intake in both models. The initial weight loss was rebounded in db/db mice, but progressed and sustained in DIO mice accompanied by circadian rises in body temperature and locomotor activity, the effects possibly balancing the elevated food intake. These results reveal that physical/metabolic states, independent of social/psychological factors, influence weight outcome of canagliflozin treatment.